Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
  • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
  • A61F2/02—Prostheses implantable into the body
  • A61F2/14—Eye parts, e.g. lenses, corneal implants; Implanting instruments specially adapted therefor; Artificial eyes
  • A61F2/141—Artificial eyes
• • C—CHEMISTRY; METALLURGY
  • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
  • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
  • C04B35/00—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
  • C04B35/01—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products based on oxide ceramics
  • C04B35/447—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products based on oxide ceramics based on phosphates, e.g. hydroxyapatite
• • C—CHEMISTRY; METALLURGY
  • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
  • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
  • C04B38/00—Porous mortars, concrete, artificial stone or ceramic ware; Preparation thereof
• • C—CHEMISTRY; METALLURGY
  • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
  • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
  • C04B38/00—Porous mortars, concrete, artificial stone or ceramic ware; Preparation thereof
  • C04B38/0051—Porous mortars, concrete, artificial stone or ceramic ware; Preparation thereof characterised by the pore size, pore shape or kind of porosity
  • C04B38/0054—Porous mortars, concrete, artificial stone or ceramic ware; Preparation thereof characterised by the pore size, pore shape or kind of porosity the pores being microsized or nanosized
• • C—CHEMISTRY; METALLURGY
  • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
  • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
  • C04B2111/00—Mortars, concrete or artificial stone or mixtures to prepare them, characterised by specific function, property or use
  • C04B2111/00474—Uses not provided for elsewhere in C04B2111/00
  • C04B2111/00836—Uses not provided for elsewhere in C04B2111/00 for medical or dental applications
• • C—CHEMISTRY; METALLURGY
  • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
  • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
  • C04B2235/00—Aspects relating to ceramic starting mixtures or sintered ceramic products
  • C04B2235/02—Composition of constituents of the starting material or of secondary phases of the final product
  • C04B2235/50—Constituents or additives of the starting mixture chosen for their shape or used because of their shape or their physical appearance
  • C04B2235/54—Particle size related information
  • C04B2235/5418—Particle size related information expressed by the size of the particles or aggregates thereof
  • C04B2235/5436—Particle size related information expressed by the size of the particles or aggregates thereof micrometer sized, i.e. from 1 to 100 micron
• • C—CHEMISTRY; METALLURGY
  • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
  • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
  • C04B2235/00—Aspects relating to ceramic starting mixtures or sintered ceramic products
  • C04B2235/60—Aspects relating to the preparation, properties or mechanical treatment of green bodies or pre-forms
  • C04B2235/602—Making the green bodies or pre-forms by moulding
  • C04B2235/6021—Extrusion moulding
• • C—CHEMISTRY; METALLURGY
  • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
  • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
  • C04B2235/00—Aspects relating to ceramic starting mixtures or sintered ceramic products
  • C04B2235/60—Aspects relating to the preparation, properties or mechanical treatment of green bodies or pre-forms
  • C04B2235/602—Making the green bodies or pre-forms by moulding
  • C04B2235/6022—Injection moulding

Definitions

• THIS INVENTION relates to an orbital implant.
• an orbital implant which includes a body of bioactive material having macropores of at least 400 ⁇ m, and a cap of bioactive material having substantially no pores or only micropores smaller than 50 ⁇ m, with the cap covering a portion of the body.
• 'b ioactive material' used in this specification has its usual generally accepted meaning or definition, namely that it is 'a mater ial that elicits a specific biological response at the interface of the material which results in the formation of a bond between the tissues and the material', as provided by L.L. Hench and J. Wilson in "An Introduction to Bioceramics", Advanced Series in Ceramics - Vol. 1 , Ed. L.L. Hench and J. Wilson, World Scientific, Singapore, New Jersey, London, Hong Kong (1 993) p. 7.
• the bioactive material may be a calcium phosphate material or compound such as a hydroxyapatite; a bioactive glass, which can typically be based on SiO 2 , Na 2 O, CaO and/or P 2 Os; a bioactive glass ceramic, which can be similar in composition to bioactive glass but which incorporates additionally MgO, CaF 2 and/or metal oxides; or a composite material comprising a polymer containing bioactive material particles, such as particles of a calcium phosphate compound, a bioactive glass and/or a bioactive glass ceramic.
• the orbital implant may preferably be spherical. It will thus be of a size so that it can be inserted into, and fit into, the orbit of a mammal, either to replace the contents of an eye following evisceration or to replace the eyeball following enucleation. Thus, when it is to be implanted into the orbit of an adult human, it may have a diameter of about 20mm.
• the macropores of the body may be substantially spherical so that they have diameters of said at least 400 ⁇ m. Preferably, the diameters of the macropores do not exceed 1 000 ⁇ m.
• Some macropores may be in communication with the outer surface of the body. In other words, when such macropores are present, the body will have irregularly spaced surface indentations or dimples. Adjacent macropores in the body may be interconnected by openings and/or passageways. Thus, by means of the macropores which are in communication with the body outer surface and the openings and/or passageways between adjacent macropores, open paths to the body outer surface, defined by the macropores, are provided in the implant body.
• the interconnecting openings or passageways between adjacent macropores may have diameters greater than 50 ⁇ m, preferably greater than 100 ⁇ m.
• the body may contain substantially no isolated or closed macropores.
• the macropores in the body may occupy from 40% to 85% by volume, preferably about 60% by volume, of the body.
• the body may also have micropores smaller than 50 ⁇ m. At least some of these micropores may be of irregular shape. Thus, they may be in the form of interstitial spaces, for example, interstitial spaces between particles of bioactive material, resulting from incomplete sintering of the particles during formation of the body.
• the sizes of these micropores are then dependent on the sizes of the bioactive material particles from which the body is sintered. However, these micropores will have a maximum dimension smaller than 50 ⁇ m, and their maximum dimension may typically be of the order of 1 ⁇ m, or even smaller. Instead, or additionally, at least some of the micropores may be of regular shape, eg substantially spherical so that their diameters are thus smaller than 50 ⁇ m.
• the micropores when present, may occupy from 3% to 70% by volume, preferably about 40% by volume, of the macropore-free bioactive material, ie the residual bioactive material around the macropores.
• All the spherical micropores present in the body may be of substantially the same size, while all the irregularly shaped micropores may be of substantially the same size.
• the irregularly shaped micropores may be smaller than the spherical micropores.
• the spherical micropores may have diameters of at least 10 ⁇ m, and may typically have diameters of 10-45 ⁇ m.
• Adjacent micropores in the body are then preferably interconnected by openings and/or passageways. Some micropores may also be interconnected to the macropores by openings and/or passageways. The micropores will thus, by means of these openings and/or passageways, provide open paths to the macropores, as well as, together with the macropores, open paths to the outer surface of the body. In other words, there may thus be substantially no isolated or closed micropores in the body.
• both interstitial micropores and spherical micropores may be present in the body, with adjacent spherical micropores being interconnected by interstitial micropores which thus constitute the interconnecting openings or passageways.
• the interstitial micropores will then also interconnect the spherical micropores to the macropores.
• the body may thus have a trimodal pore size distribution, comprising macropores, which may be in the size range 400-1 OOO ⁇ m; larger micropores which may be in the size range smaller than 50 ⁇ m but at least 10 ⁇ m; and smaller micropores which are 1 ⁇ m or smaller.
• the cap may, in one embodiment of the invention, be of bioactive material containing substantially no pores.
• the cap may contain pores; however, the pores will then be micropores smaller than 50 ⁇ m, ie the pores will then be irregular micropores and/or spherical micropores, as hereinbefore described.
• the cap is then characterized thereby that it contains no pores larger than 50 ⁇ m. Thus, it will contain no macropores as hereinbefore described.
• the cap which is thus an anterior cap, may be in the form of a circular concave or dish-shaped disc integrated with or embedded in the body of bioactive material.
• the diameter of the rim of the cap may be the same as the diameter of the implant; however, preferably, it has a smaller diameter than that of the implant. Preferably, the diameter of the rim of the cap may be about three-quarters that of the implant.
• the cap will thus be thin relative to the diameter of the implant.
• its thickness may be no more than half the diameter of the implant, and preferably about one-fortieth of the diameter of the implant.
• bioactive material of the cap can, at least in principle, be different to that of the body, it is envisaged that the body and the cap will normally be of the same bioactive material.
• the bioactive material may, in particular, be synthetic hydroxyapatite.
• the orbital implant of the invention is thus, in use, placed into an orbit of a mammal.
• an orbital implant of the integrated type ie an orbital implant which, in use, becomes integrated through tissue ingrowth and vascularization, such as that of the invention, following evisceration or enucleation, is known.
• the mammal will thus be one who has had an ocular enucleation or evisceration, or who needs an implant replacement.
• Use of the orbital implant according to the invention will, it is believed, result in fibrovascular tissue ingrowth into the entire body of the implant, with the comparatively smooth cap resulting in little or no erosion of anterior tissue, including the conjunctiva, taking place.
• eye muscles are typically attached to the implant, whereafter the implant is covered with tissue including conjunctiva, and a period of healing allowed during which fibrovascular tissue ingrowth into the implant occurs. Thereafter, an artificial eye or prosthesis can be fitted over the conjunctiva, adjacent the cap of the implant. It follows thus that when the implant is placed into the orbit, it is orientated such that the cap faces anterior tissue including the conjunctiva.
• FIGURE 1 shows a front view of an orbital implant according to one embodiment of the invention
• FIGURE 2 shows a side view of the orbital implant of Figure 1
• FIGURE 3 shows an enlarged cross-sectional view of part of the orbital implant of Figure 1 ;
• FIGURE 4 shows an enlarged cross-sectional view, similar to that of Figure 3, of an orbital implant according to another embodiment of the invention.
• FIGURE 5 shows a portion of the cross-sectional view of Figure 4, enlarged even further.
• reference numeral 10 generally indicates an orbital implant according to one embodiment of the invention.
• the implant 10 is substantially spherical, and has a diameter of about 20mm. It includes a body 12 of synthetic hydroxyapatite having spherical macropores 14 as well as spherical micropores 1 6.
• the macropores 14 are all of substantially the same size, and have diameters of 400-1 OOO ⁇ m, typically about 800 ⁇ m.
• the macropores 14 occupy about 60 vol % of the body 1 2.
• Some of the macropores 14 are in communication with the outer surface 15 of the body 12, as can be seen in Figure 3. It will be appreciated that at least some adjacent macropores may be interconnected (not shown) by openings or passageways (not shown).
• the micropores 1 6 are also all of substantially the same size, and have diameters less than 50 ⁇ m, eg about 10-45 ⁇ m.
• the micropores 1 6 occupy about 40 vol % of the residual hydroxyapatite, ie the hydroxyapatite material between the macropores 14.
• the body 1 2 is thus solid save for the macropores and micropores therein.
• the implant 10 also includes a thin anterior cap 18 of hydroxyapatite material having no macropores.
• the cap 18 thus contains either no pores at all or only micropores (not shown) having maximum dimensions less than 50 ⁇ m, eg having maximum dimensions of about 1 ⁇ m. When present, the micropores will occupy about 40% by volume of the cap material.
• the cap 1 8 is thus characterized thereby that it contains no pores larger than 50 ⁇ m.
• the cap 18 is in the form of a concave dish, and the rim 20 of the cap 18 has a diameter of about three-quarters that of the implant 10. Thus, when the implant 10 has a diameter of about 20mm, the rim 20 of the cap 18 has a diameter of about 15mm.
• the thickness of the cap 1 8 is about one-fortieth the diameter of the implant 10.
• the thickness of the cap 18 will be about 0.5mm.
• reference numeral 100 generally refers to an orbital implant according to another embodiment of the invention.
• the implant 100 is also substantially spherical (not shown), and has a body 1 2 and an anterior cap (not shown) as hereinbefore described in respect of the implant 10.
• the body 12 of the implant 100 also has spherical macropores 14; however, apart from some of the macropores 14 of the implant 100 being in communication with the outer surface of the body 1 2 of the implant 100 (as hereinbefore described in respect of the implant 10) adjacent macropores 14 are interconnected by openings 102.
• the diameters of the openings 102 are typically about 100 ⁇ m or greater.
• the implant 100 is normally manufactured by a sintering process such as that hereinafter described, and the interconnection of adjacent macropores then typically arises as a result of adjacent macropores coalescing together during the sintering process.
• a sintering process such as that hereinafter described
• the interconnection of adjacent macropores then typically arises as a result of adjacent macropores coalescing together during the sintering process.
• the common openings 102 between adjacent macropores 14 and the macropores 14 which are in communication with the outer surface of the implant body, open paths to the body outer surface are defined by the macropores in the body 1 2.
• the body 1 2 contains substantially no closed or isolated macropores.
• the body 1 2 of the implant 100 also contains spherical micropores 1 6 (see Figure 5), as hereinbefore described in respect of the implant 10. Moreover, it also contains irregular micropores 104 in the form of interstitial spaces between hydroxyapatite particles 106, resulting from incomplete sintering of hydroxyapatite particles 106 during formation of the body 1 2 by means of a sintering process such as that hereinafter described. Although the hydroxyapatite particles are shown, in Figure 5, as distinct separate particles, this is for ease of illustration only.
• adjacent particles will thus be partially sintered together so that such adjacent particles can no longer be viewed as being distinct particles (as shown in Figure 5) but rather merge so that they are in the form of an agglomerated mass containing the spherical macropores 14, the spherical micropores 1 6 and the irregular micropores 104.
• the sizes of the micropores 104 are substantially the same, and are dictated by the sizes of the hydroxyapatite particles 106 used for sintering. Thus, when the particle sizes are about 1 ⁇ m, the maximum dimensions of the micropores 104 may be about 1 ⁇ m, or smaller.
• Adjacent micropores 1 6 and 104 are thus interconnected. Typically, adjacent micropores 1 6 are interconnected by micropores 104. Additionally, the micropores 104 and/or the micropores 16 are also interconnected to the macropores 14. Thus, the micropores 16, 104 together with the macropores 14, also define open paths to the outer surface of the implant body 12. There are thus substantially no closed or isolated micropores 1 6, 104 in the implant body.
• the irregular micropores 104 typically occupy about 40% by volume of the residual hydroxyapatite, ie the macropore free hydroxyapatite, while the spherical micropores 16 typically occupy about 10% by volume of the residual hydroxyapatite.
• a mixture A is prepared by compounding hydroxyapatite powder having a mean particle size of about 1 ⁇ m, with a polymeric binder of a type suitable for injection moulding or extrusion; grinding the mixture to less than 300 ⁇ m particle size; and mixing stearic acid balls with a size distribution between 500-1 OOO ⁇ m therewith.
• a mixture B is prepared by compounding hydroxyapatite powder having a mean particle size of about 1 ⁇ m with the same polymeric binder as used for mixture A; and grinding the mixture to less than 300 ⁇ m particle size.
• the mixture A is loaded into a die suitable for pressing of a sphere.
• This die includes a piston which will create a depression on the surface of the sphere during pressing, with the depression having the size and shape of the desired cap 1 8.
• the mixture A is lightly pressed to form a sphere containing the said depression.
• the depression is then filled with a correct amount of the mixture B.
• the structure including the sphere with powder is consolidated by pressing to form a spherical compact comprising mixture A with an intimately bound cap of mixture B.
• the structure is sintered at a temperature below 1 10O°C.
• interstitial micropores 104 which result from incomplete sintering of adjacent hydroxyapatite particles, will thus normally be present.
• interstitial micropores will also be present in the body 12 of the implant 10 when it is manufactured by means of such a sintering process.
• the implants 10, 100 can be implanted into the orbit or eye socket of a human who has had an ocular enucleation or evisceration, or who needs an implant replacement.
• the implants can be placed according to known procedures for integrated implants.
• the implant is implanted to replace the eye contents.
• the implant is placed without covering or with a covering or wrapping of tissue or artificial material into the eye muscle cone (not shown), and the eye muscles attached directly to the implant 10, 100 or to the implant wrapping. Instead, the eye muscles can be wrapped around the implant 10, 100 and secured together without direct attachment of the eye muscles to the implant 10, 100.
• the anterior surface of the implant is covered with tissue including the conjunctiva.
• the cap 18 faces the conjunctiva.
• a healing period is then allowed.
• fibrovascular tissue ingrowth into the entire body 1 2 is promoted by the bioactive hydroxyapatite surfaces in conjunction with the open paths provided by the macropores 14, the micropores 1 6 and the micropores 104.
• the implant is integrated and, due to the muscle attachment, capable of movement.
• the prosthesis ie an artificial eye, is located in position adjacent the cap 18, to obtain an artificial eye with natural appearance and good motility.
• the orbital implant of this invention addresses two common causes of complications associated with the use of orbital implants of the integrated type. These are incomplete fibrovascular tissue ingrowth into the implant interior and erosion of anterior tissue by rough surface protrusions of a porous body.
• the orbital implant of this invention addresses the first of these causes of complications by promoting complete ingrowth of fibrovascular tissue into the implant interior. This is achieved by the implant of the invention having three modified material properties, as compared to properties commonly encountered in known porous orbital implants:
• the macropore size is substantially increased, by a factor of 2 to 5, over that commonly encountered in known porous orbital implants.
• Macropore size is generally restricted in porous orbital implants, to achieve improved mechanical properties and an even external roundness. This is particularly important when the implant is made from materials derived from natural sources such as coral or processed bovine bone, where the external shape has to be achieved by machining. With such materials, the external roundness can be extremely uneven due to the fracture of brittle protrusions and pore edges during machining. It also produces undesirable sharp fracture surfaces.
• an even roundness is readily achieved due to the entirely synthetic manufacture thereof, which eliminates any need for machining of a brittle surface and thereby avoids protrusions with sharp fracture surfaces.
• this larger macropore size is associated with a corresponding increase in the size of the interconnecting openings between adjacent macropores, to the extent that even the interconnecting openings are larger than the macropores commonly encountered in known porous orbital implants.
• the orbital implant of the invention can have an engineered distribution of open micropores along the macropore surfaces and in the bulk of the ceramic material. These micropores are present in a very high volume fraction, typically 40 vol % of the macropore-free hydroxyapatite material.
• This engineered micropore distribution distinguishes the orbital implant of this invention over known bioceramic orbital implant materials, where microporosity is either absent in the material source or regarded as detrimental to mechanical strength and therefore eliminated to a large extent.
• the small micropore size present at high volume fraction serves to significantly increase surface roughness at the cellular level. It further achieves an increase in surface area, up to a factor of 70, over that of an equivalent material without the micropore distribution.
• the large macropore size combined with large interconnecting opening size result in open access for fluid and tissue ingrowth to the central regions of the implant.
• the material has been engineered to exhibit high surface roughness, high surface area, strong capillary force and inherent bioactivity. This ensures immediate strong tissue attachment, elimination of micromotion, rapid ingress and retention of fluid with improved cell attachment, direct tissue apposition without intervening fibrous tissue.
• the orbital implant of this invention further addresses the second cause of complications associated with porous orbital implants of the integrated type. This is the tendency of porous materials to present a rough surface with sharp protrusions to anterior tissue, leading to erosion of the tissue and complications such as exposure of the implant.
• a cap of comparative smoothness the implant does not present sharp edges to anterior tissue. This serves to avoid erosion of the anterior tissue.
• the cap is an integral part of the implant structure and is comprised of the same material as the implant body, incorporating the same micropore distribution as described.
• a polymer cap will exhibit low or no bioactivity and will require some different means to achieve attachment of the anterior tissue. It is also different from a temporary resorbable coating over the implant, such as a polymer- or inorganic cement-based cap, since a resorbable coating will merely delay ingrowth and ongrowth to the ceramic while the underlying roughness of the porous body will eventually present again. Finally, it is extremely difficult or impossible from a ceramic processing point of view to attach and incorporate such a cap on pre-densified material, such as a coral-derived or bone-derived material.
• the implant body with incorporated cap does not present sharp and rough edges to the anterior tissue, thereby avoiding erosion of the anterior tissue.
• full incorporation of the cap is advantageous in that it presents a seamless transition from porous body to cap from a tissue engineering and materials point of view.
• the cap material exhibits high surface area, suitable roughness at the cellular level only, strong capillary force and inherent high bioactivity. These properties jointly promote tissue attachment, elimination of micromotion, rapid ingress and retention of fluid with improved cell attachment, direct tissue apposition without intervening fibrous tissue.

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• Chemical & Material Sciences (AREA)
• Engineering & Computer Science (AREA)
• Ceramic Engineering (AREA)
• Health & Medical Sciences (AREA)
• Materials Engineering (AREA)
• Structural Engineering (AREA)
• Organic Chemistry (AREA)
• Transplantation (AREA)
• Oral & Maxillofacial Surgery (AREA)
• Vascular Medicine (AREA)
• Ophthalmology & Optometry (AREA)
• Cardiology (AREA)
• Manufacturing & Machinery (AREA)
• Biomedical Technology (AREA)
• Heart & Thoracic Surgery (AREA)
• Nanotechnology (AREA)
• Life Sciences & Earth Sciences (AREA)
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• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Materials For Medical Uses (AREA)
• Prostheses (AREA)
• Steroid Compounds (AREA)

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